U.S. patent application number 10/816677 was filed with the patent office on 2005-10-06 for controlled delivery of therapeutic agents from medical articles.
Invention is credited to Chin, Yem, Dao, Kinh-Luan (Lenny), Panos, Anastasia, Zhong, Sheng-Ping (Samuel).
Application Number | 20050220853 10/816677 |
Document ID | / |
Family ID | 35054589 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050220853 |
Kind Code |
A1 |
Dao, Kinh-Luan (Lenny) ; et
al. |
October 6, 2005 |
Controlled delivery of therapeutic agents from medical articles
Abstract
The present invention provides novel adenosine receptor
antagonists, more particularly, A.sub.1 adenosine receptor
antagonists. Pharmaceutical compositions comprising an A.sub.1
adenosine receptor antagonist disclosed herein and a
pharmaceutically acceptable carrier are further provided.
Compositions also include diagnostic assay-type probes comprising a
novel A.sub.1 adenosine receptor antagonist that is labeled or
conjugated with radioactive or non-radioactive material. Methods
for treating A.sub.1 adenosine receptor related disorders
comprising administering an A.sub.1 adenosine receptor antagonist
of the invention are also disclosed. The novel A.sub.1 adenosine
receptor antagonist compositions find further use in diagnostic and
imaging methods.
Inventors: |
Dao, Kinh-Luan (Lenny);
(Randolph, MA) ; Panos, Anastasia; (Worcester,
MA) ; Chin, Yem; (Burlington, MA) ; Zhong,
Sheng-Ping (Samuel); (Shrewsbury, MA) |
Correspondence
Address: |
MAYER, FORTKORT & WILLIAMS, PC
251 NORTH AVENUE WEST
2ND FLOOR
WESTFIELD
NJ
07090
US
|
Family ID: |
35054589 |
Appl. No.: |
10/816677 |
Filed: |
April 2, 2004 |
Current U.S.
Class: |
424/449 |
Current CPC
Class: |
A61L 27/54 20130101;
A61L 2300/622 20130101; A61K 9/7023 20130101; A61L 29/16 20130101;
A61L 31/16 20130101; A61L 2300/45 20130101; A61L 2300/258
20130101 |
Class at
Publication: |
424/449 |
International
Class: |
A61K 009/70 |
Claims
1. A medical article comprising: (a) an adhesive region comprising
an adhesive; and (b) a therapeutic agent, wherein said therapeutic
agent is adhered to a surface of said adhesive region, with the
proviso that said therapeutic agent is adhered to said surface of
said adhesive region in a form other than within spray dried
microparticles that comprise said therapeutic agent and a carrier
polymer.
2. The medical article of claim 1, wherein said adhesive is a
curable adhesive.
3. The medical article of claim 2, wherein said adhesive is a
curable, protein-based adhesive.
4. The medical article of claim 1, wherein said adhesive is a
pressure-sensitive adhesive.
5. The medical article of claim 1, wherein said adhesive is a
solvent assisted adhesive.
6. The medical article of claim 1, wherein said therapeutic agent
is adhered to said adhesive region in the absence of said
microparticles.
7. The medical article of claim 6, wherein said therapeutic agent
is applied in powder form to said adhesive region.
8. The medical article of claim 6, wherein at least a portion of
said adhesive region is biodisintegrable.
9. The medical article of claim 1, further comprising
microparticles at least a portion of which are attached to said
surface of said adhesive region.
10. The medical article of claim 9, wherein said microparticles are
microspheres.
11. The medical article of claim 10, wherein said microspheres have
a number average diameter between 0.1 to 50 .mu.m.
12. The medical article of claim 9, wherein said medical article
comprises at least two populations of microparticles that are of
different composition from one another.
13. The medical article of claim 9, wherein said medical article
comprises at least two populations of microparticles having
different size distributions.
14. The medical article of claim 9, at least a portion of said
therapeutic agent is attached to or is partially or fully
encapsulated within said microparticles.
15. The medical article of claim 14, wherein said microparticles
are biodisintegrable.
16. The medical article of claim 9, at least a portion of said
therapeutic agent is neither attached to nor partially or fully
encapsulated within said microparticles.
17. The medical article of claim 16, wherein said medical article
is provided by a process in which said therapeutic agent is admixed
in powder form with said microparticles and applied to said
adhesive region.
18. The medical article of claim 16, wherein said medical article
is provided by a process in which said microparticles are applied
to said adhesive region in powder form, followed by the application
of said therapeutic agent in powder form.
19. The medical article of claim 16, wherein said microparticles
are biostable.
20. The medical article of claim 16, wherein said microparticles
are biodisintegrable.
21. The medical article of claim 16, wherein at least a portion of
said therapeutic agent is unadhered to said adhesive region and
occupies interstices between said microparticles.
22. The medical article of claim 16, wherein at least a portion of
said therapeutic agent is adhered to said adhesive region.
23. The medical article of claim 22, wherein said adhesive region
is biodisintegrable.
24. The medical article of claim 1, wherein said medical article
further comprises an additional biodisintegrable adhesive region
over said therapeutic agent.
25. The medical article of claim 24, further comprising additional
therapeutic agent adhered to a surface of said additional adhesive
region.
26. The medical article of claim 1, further comprising a medical
article substrate, wherein said adhesive region is disposed in a
layer over at least a portion of said medical article
substrate.
27. The medical article of claim 1, wherein said medical article
comprises first and second distinct adhesive regions, which may be
of the same or of different composition.
28. The medical article of claim 1, wherein said medical article
comprises first and second therapeutic agents of different
composition.
29. The medical article of claim 9, wherein said medical article
comprises first and second populations of microparticles of
different composition.
30. The medical article of claim 9, wherein said medical article
comprises first and second populations of microparticles of
different size distribution.
31. The medical article of claim 1, wherein said therapeutic agent
is a high-molecular-weight therapeutic agent.
32. The medical article of claim 31, wherein said
high-molecular-weight therapeutic agent is a
polynucleotide-containing therapeutic agent.
33. The medical article of claim 1, wherein said adhesive is mussel
protein adhesive.
34. The medical article of claim 9, wherein said medical article
comprises: (a) a first therapeutic agent and a first population of
microparticles adhered to a surface of a first adhesive region; and
(b) a second therapeutic agent and a second population of
microparticles adhered to a surface of said a second adhesive
region which is distinct from said first adhesive region, wherein
said first and second adhesive regions may be of the same or
different compositions, wherein said first and second therapeutic
agents may be of the same or different compositions, and wherein
said first and second populations of microparticles may be of the
same or different composition or of the same or different size
distribution.
35. The medical article of claim 34, wherein said first and second
adhesive regions are of different composition.
36. The medical article of claim 34, wherein said first and second
therapeutic agents are of different composition.
37. The medical article of claim 34, wherein said first and second
populations of microparticles are of different composition.
38. The medical article of claim 34, wherein said first and second
populations of microparticles are of different size
distribution.
39. The medical article of claim 9, further comprising a
biodisintegrable layer over said therapeutic agent and said
microparticles.
40. The medical article of claim 1, wherein said medical article is
an implantable or insertable medical device.
41. The medical article of claim 40, wherein said implantable or
insertable medical device is selected from a balloon, a catheter, a
stent, a patch, a heart valve, a bone prosthesis, a pacemaker, a
vena cava filter, and an abnormal abdominal aneurism device.
42. The medical article of claim 40, wherein said implantable or
insertable medical device further comprises a biodisintegrable
protection layer disposed over said therapeutic agent to protect
said therapeutic agent during device delivery.
Description
RELATED APPLICATION DATA
[0001] This application is related to U.S. Ser. No. 10/638,564
filed Aug. 11, 2003 and entitled "MEDICAL DEVICES COMPRISING SPRAY
DRIED MICROPARTICLES," which is incorporated by reference herein in
its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to medical articles that are
useful for the controlled delivery of therapeutic agents, including
high-molecular-weight therapeutic agents.
BACKGROUND OF THE INVENTION
[0003] Percutaneous transluminal coronary angioplasty ("PTCA" or
"angioplasty") procedures have been performed for many years as an
adjunct to correcting vascular disease in patients. Angioplasty
procedures commonly involve the insertion of a catheter having a
balloon through the patient's vascular system until the balloon is
positioned across a lesion or blockage in a coronary artery. The
balloon is then inflated to compress the lesion or blockage against
the arterial walls, thereby opening the artery for increased blood
flow.
[0004] In some instances, however, the goal of the angioplasty
procedure is defeated at least in part by a complete or partial
reclosure of the artery at or near the compressed lesion or
blockage. Two mechanisms are believed to be principally responsible
for reclosure of the artery. The first mechanism is recoil, which
is a mechanical process involving the elastic rebound of the
compressed lesion or blockage. The second mechanism is restenosis,
which is believed to be caused by proliferation of the smooth
muscle cells present in the artery walls near the lesion or
blockage. Restenosis can occur over a period of several weeks or
months after the PTCA procedure.
[0005] Many different methods have been employed to limit the
effects of restenosis, including radiation treatments and various
drug therapies, delivered locally and systemically, to slow
proliferation of the smooth muscle cells. Recoil of the arterial
walls can be prevented by using stents, which can be temporarily or
permanently deployed within the artery to mechanically maintain
patency of the artery. Stents are very effective at carrying out
this task; however, they may also irritate the contacting arterial
walls, thereby encouraging restenosis.
[0006] Gene therapy has been used for diverse medical purposes,
including slowing the proliferation of smooth muscle cells. Genes
are usually delivered into a patient's cells through a vector, for
example, a retroviral vector whose DNA is genetically engineered to
include a desired DNA sequence. Alternatively, nonviral gene
transfer methods can be used, for example, plasmid DNA vectors
(which can be delivered, for example, along with polymeric
carriers, DNA condensing agents, lipofection agents, receptor
mediated delivery vectors, and so forth).
[0007] Hence, incorporation of DNA molecules into the coronary
artery walls near the treatment site in connection with angioplasty
can be beneficial to inhibit restenosis. Moreover, a stent can be
used as the delivery vehicle for the DNA, while at the same time
maintaining the patency of the artery following PTCA.
[0008] One way to control the release of therapeutic agents,
including DNA or other high-molecular-weight therapeutic agents,
from stents or other medical articles is to first
precipitate/deposit the therapeutic agent onto the surface of the
medical article, and to subsequently provide a polymeric barrier
layer over the therapeutic agent. This method, however, can be
limited by a low affinity of the surface of the medical article for
the therapeutic agent, and vice versa. For example, medical devices
surfaces, including a wide range of metallic and polymeric
surfaces, are commonly hydrophobic. Various therapeutic agents,
including polynucleotides such as DNA and RNA, on the other hand,
are relatively hydrophilic, leading to limited surface coverage and
to loss of the therapeutic agent.
[0009] In addition, certain polymers that are highly biocompatible
(e.g., polystyrene-polyisobutylene copolymers) may in some
instances provide insufficient mass transport of therapeutic
agents, particularly high-molecular-weight therapeutic agents such
as polynucleotides, after deployment, thereby limiting the
efficiency and control of the therapeutic-agent release.
[0010] Accordingly, there is a need for coatings for stents and
other medical articles which release therapeutic agents, including
high-molecular-weight therapeutic agents such as polynucleotides,
in a controlled fashion, and which do not suffer from the foregoing
and other disadvantages.
SUMMARY OF THE INVENTION
[0011] The above and other challenges are met by the present
invention. According to one aspect of the present invention,
medical articles are provided which comprise the following: (a) an
adhesive region comprising an adhesive, (b) a therapeutic agent and
(c) optional microparticles. In this aspect of the invention, the
therapeutic agent, the optional microparticles, or both the
therapeutic agent and the optional microparticles are adhered to
the adhesive region.
[0012] In certain embodiments, the medical article further
comprises a substrate, for example, a polymeric, ceramic or
metallic substrate, with the adhesive region disposed in a layer
over at least a portion of the medical article substrate.
[0013] Upon placement of such medical articles at a position on or
within a patient, therapeutic agent is released from the medical
article and into the patient. Examples of medical articles include,
for instance, implantable or insertable medical devices.
[0014] Other aspects of the present invention are directed to
methods of providing such medical articles.
[0015] An advantage of the present invention is that medical
articles can be provided, which regulate the release of therapeutic
agents, including polynucelotides and other high-molecular-weight
therapeutic agents, from a medical article to a patient.
[0016] Another advantage of the present invention is that medical
articles can be provided which exhibit increased adherence between
the therapeutic agents and polymeric and non-polymeric substrate
surfaces of the medical articles, thereby increasing coating
efficiency.
[0017] Another advantage of the present invention is that existing
medical devices can be readily modified to provide them with
therapeutic-agent releasing coatings.
[0018] These and other aspects, embodiments and advantages of the
present invention will become immediately apparent to those of
ordinary skill in the art upon review of the Detailed Description
and claims to follow.
DETAILED DESCRIPTION OF THE INVENTION
[0019] According to one aspect of the present invention, medical
articles are provided which contain the following: (a) one or more
adhesive regions, each containing one or more adhesives, (b) one or
more therapeutic agents, and (c) optional microparticles. In this
aspect of the invention, the therapeutic agent, the optional
microparticles, or both the therapeutic agent and the optional
microparticles are adhered to the adhesive region.
[0020] "Adhesives," as the term is used herein, are materials that
are capable of binding therapeutic agents and microparticles upon
contact with the same. The adhesives utilized in connection with
the present invention include the following: (1) Adhesives that are
inherently capable of adhesion upon contact with therapeutic agents
and with the optional microparticles (referred to herein as
"pressure-sensitive adhesives") (an everyday example of a pressure
sensitive adhesive is the adhesive that is provided on an adhesive
tape). (2) Adhesives that adhere upon contact with therapeutic
agents and with the optional microparticles due to the presence of
residual solvent, and that maintain adhesion subsequent to solvent
removal (referred to herein as "solvent assisted adhesives"). (3)
Adhesives that adhere upon contact with therapeutic agents and with
the optional microparticles (due to the tackiness of the uncured
adhesive), and which display increased adhesion after the adhesive
undergoes a curing process (referred to herein as "curable
adhesives"). In the latter case, the physical properties of the
adhesive change as a result of chemical reactions that occur during
curing (e.g., crosslihking and/or other reactions, based, for
instance, on condensation, addition, substitution, and/or other
reaction mechanisms). Chemical reaction within curable adhesives
can be brought about in a number of ways known in the adhesive art,
including the application of energy (e.g., heat, ultraviolet
radiation or other radiation), the presence of an external chemical
reactant or co-reactant (e.g., moisture-induced polymerization in
the case of cyanoacrylates, and co-reactant-based polymerization in
the case of two-component urethanes and two-component epoxies,
among others), the removal of a solvent (e.g., upon drying), and so
forth. The adhesives for use in the present invention include those
that maintain their adhesive properties, whether wet or dry.
[0021] Suitable curable adhesives for use in connection with the
present invention include synthetic and natural adhesives, which
can be selected from one or more of the following among others:
cyanoacrylates, epoxy-based adhesives, urethane-based adhesives,
mussel adhesive proteins, fibrin glues, thrombin-based adhesives,
silk-based adhesives, elastin-based adhesives, collagen-based
adhesives, casein-based adhesives, gelatin-based adhesives,
albumin-based adhesives, keratin-based adhesives, chitin-based
adhesives, and chitosan-based adhesives, including natural proteins
in combination with aldehyde or other crosslinkers (e.g.,
albumin-glutaraldehyde adhesives, gelatin-resorcinol-formaldehyde
adhesives, and so forth).
[0022] In certain embodiments protein-based adhesives are utilized.
A particularly desirable curable adhesive is mussel protein
adhesive. The foot of the common mussel (Mytilus edulis) produces
an adhesive that keeps the shelled organism anchored to rocks and
other objects, allowing them to withstand the extreme pounding of
waves. Chemical analysis of this natural, under-water-curable,
water-proof glue has shown that the key to its adhesive properties
is a unique compound called mussel adhesive protein, which contains
a high concentration of an amino acid, DOPA
(dihydroxyphenylalanine). Once secreted, mussel adhesive protein
undergoes an in-situ crosslinking or hardening reaction, which
leads to the formation of a solid adhesive that clings to wet
surfaces with extraordinary strength.
[0023] Suitable pressure-sensitive adhesives for use in connection
with the present invention include synthetic and natural adhesives,
which can be selected from one or more of the following:
hydrocolloid-based adhesives, acrylic based adhesives (e.g., 0175
Adhesive, Spectrum.TM. and Spectrum Plus.TM. from Velcro USA,
Inc.), rubber-based adhesives, including natural rubber,
polyisoprene, polyisobutylene, butyl rubber, acrylonitrile rubber,
etc. (e.g., 19 Adhesive, Tempo.TM. and Vector.TM. from Velcro USA,
Inc.), styrene-block-copolymer-based pressure-sensitive adhesives
such as styrene-isoprene-styrene and styrene-butadiene-styrene
block copolymer adhesives, silicone-based pressure-sensitive
adhesives, and polyurethane-based pressure-sensitive adhesives,
among others.
[0024] Suitable solvent-assisted adhesives for use in connection
with the present invention include a wide range of synthetic and
natural polymers, and can be selected from the polymeric materials
listed below for use in microparticles.
[0025] In some embodiments of the invention, the adhesive region is
in the form of an adhesive layer that covers all or a part of an
underlying medical article substrate (e.g., where a metal
substrate, such as a stent, or a polymeric substrate, such as a
balloon or a patch, is coated with an adhesive layer in accordance
with the present invention). As used herein a "layer" of a given
material is a region of that material whose thickness is small
compared to both its length and width. As used herein, a layer need
not be planar, for example, taking on the contours of an underlying
substrate. Layers can be discontinuous (e.g., patterned). Terms
such as "film," "layer" and "coating" may be used interchangeably
herein. In other embodiments of the invention, the adhesive region
corresponds to a component of a medical device. In still other
embodiments, the adhesive region corresponds to the bulk of a
medical article (e.g., where the adhesive region is cast in the
form of a medical article using a mold or other template).
[0026] Methods by which an adhesive layer may be provided on an
underlying substrate (e.g., a medical article substrate or a
releasable substrate such as a mold or other template) are varied
and include the following methods, among others: spraying
techniques, roll and brush coating techniques, dipping techniques,
spin coating techniques, web coating techniques, techniques
involving coating via mechanical suspension such as air suspension,
ink jet techniques, and electrostatic techniques. In some
embodiments, layers are repeatedly applied to build up the
thickness of the adhesive region.
[0027] In some embodiments of the invention, the adhesive region is
a biodisintegrable adhesive region. As a result, the release of the
therapeutic agent and/or optional microparticles is modulated
based, at least in part, upon the disintegration rate of the
adhesive region. This is advantageous, for example, because the
therapeutic agent and/or microparticles are securely bonded to the
medical article during delivery; at the same time, however, the
rate at which the therapeutic agent and/or microparticles are
released from the medical article is controlled. As used herein, a
"biodisintegrable" adhesive is an adhesive which undergoes
dissolution, degradation, resorption and/or other disintegration
processes upon administration to a patient.
[0028] As noted above, in the medical articles of the present
invention, therapeutic agent, the microparticles, or both the
therapeutic agent and microparticles are adhered to the adhesive
region. Hence, variations of the present invention include the
following, among others: (a) the therapeutic agent is adhered to
the adhesive region in the absence of the microparticles; (b) the
medical article includes both therapeutic agent and microparticles,
and the therapeutic agent is at least partially embedded or
otherwise encapsulated within or attached to the microparticles,
which are in turn adhered to the adhesive region; and (c) the
medical article includes both therapeutic agent and microparticles,
and the therapeutic agent is not at least partially embedded or
otherwise encapsulated within or attached to the microparticles, in
which case (i) the therapeutic agent and microparticles are both
adhered to the adhesive region or (ii) the microparticles are
adhered to the adhesive region and the therapeutic agent occupies
interstices between the microparticles.
[0029] In some embodiments, the therapeutic agent and/or
microparticles are applied in powder form to the surface of the
adhesive region. Examples include: (a) applying the therapeutic
agent and/or microparticles in powder form to a pressure-sensitive
adhesive region, (b) applying the therapeutic agent and/or
microparticles in powder form to the surface of a solvent-assisted
adhesive that contains residual solvent, followed by solvent
removal, and (c) applying the therapeutic agent and/or
microparticles in powder form to an uncured adhesive region,
followed by curing. Examples of techniques by which therapeutic
agent and/or microparticles may be applied in powder form include,
for example, spraying techniques, fluidized coating techniques,
rapid prototyping head techniques, techniques involving
rolling/dipping into powder, and so forth.
[0030] In some embodiments, the therapeutic agent and/or
microparticles are dissolved or dispersed within a fluid (e.g.,
water and/or an organic solvent) which is applied to the adhesive
region (e.g., by spraying techniques, roll and brush coating
techniques, dipping techniques, spin coating techniques, web
coating techniques, techniques involving coating via mechanical
suspension such as air suspension, ink jet techniques,
electrostatic techniques, etc.).
[0031] In some embodiments, the therapeutic agent and/or
microparticles are applied to the adhesive region using a
combination of the above techniques (e.g., applying the
microparticles in powder form to the adhesive region, followed by
application of a solution or dispersion of the therapeutic
agent).
[0032] Steps of (a) applying an adhesive region, followed by (b)
applying therapeutic agent and/or microparticles can be repeated as
desired, thereby creating alternating regions of adhesive and
therapeutic agent/microparticles. In these embodiments, the
adhesive region is beneficially a biodisintegrable adhesive region,
thereby promoting release of the therapeutic agent over time.
[0033] Numerous variations are possible in embodiments of the
invention where the therapeutic agent is provided in conjunction
with microparticles that are adhered to the adhesive region. For
example, microparticles and therapeutic agent can be applied to the
surface of the adhesive region, either sequentially or
concurrently.
[0034] Where the microparticles and the therapeutic agent are
applied sequentially, examples include the following: (A)
Application of the therapeutic agent, followed by application of
the microparticles, followed by solvent removal (in the case of a
solvent assisted adhesive) or cure (in the case of a curable
adhesive). Where a pressure sensitive adhesive is employed, no such
final step is needed. (B) Application of the microparticles,
followed by application of the therapeutic agent, followed by
solvent removal (in the case of a solvent assisted adhesive) or
cure (in the case of a curable adhesive). Again, where a pressure
sensitive adhesive is employed, no such final step is needed. (C)
Application of the microparticles, followed by solvent removal (in
the case of a solvent assisted adhesive) or cure (in the case of a
curable adhesive), followed by application of the therapeutic agent
to the attached microparticle layer.
[0035] Where the microparticles and the therapeutic agent are
provided concurrently, they are either provided as separate
entities (e.g., where the microspheres create adjacent pockets
which are occupied by the therapeutic agent and from which the
therapeutic agent is released), or they are provided as a combined
entity (e.g., where the therapeutic agent is at least partially
embedded or otherwise encapsulated within or attached to the
microparticles). In embodiments wherein the therapeutic agent is at
least partially embedded or otherwise encapsulated within or
attached to the microparticles (e.g., where the microparticles
provide a drug delivery matrix within which the therapeutic agent
is dispersed, or where the microparticles include an inner region
comprising the therapeutic agent which is encapsulated by another
material, or where the therapeutic agent is attached to the surface
of the microparticle, etc.), the therapeutic agent is commonly
released from the microparticles by diffusing from the
microparticles, by biodisintegration of the microparticles, by
cleavage of a bond between the microparticles and the therapeutic
agent, and so forth.
[0036] Microparticles for use in connection with the present
invention are available in a wide range of shapes, sizes, and
compositions. Microparticles of different sizes and/or of different
shapes and/or of different compositions can be admixed within a
single microparticle-containing region, if desired. Moreover, in
embodiments where two or more distinct microparticle-containing
regions are provided (e.g., separate microparticle-containing
regions lying over one another or separate microparticle-containing
regions lying adjacent to one another) the regions can comprise
microparticles of different sizes and/or of different shapes and/or
of different compositions.
[0037] Microparticle shapes include spherical, rod shaped,
irregular, and so forth. Microparticles can be solid or hollow.
[0038] Average (e.g., weight average) microparticle size typically
ranges from 10 nm to 1000 .mu.m, more typically from 0.1 to 50
.mu.m, in largest linear cross-sectional dimension (i.e., the
diameter in the case of microspheres, the length in the case of
filamentous microparticles, etc.). In many embodiments, the release
rate of the therapeutic agent depends upon the size of the
microparticles. For example, bigger particles create bigger pockets
for occupation by the therapeutic agent and therefore can modulate
release. As another example, where the microparticles provide a
drug delivery matrix within which the therapeutic agent is
dispersed, bigger particles present longer paths for diffusion
and/or take longer to disintegrate, again modulating release.
[0039] In certain embodiments, the microparticles utilized either
inherently have a surface charge, or they are provided with one.
The presence of a surface charge on the microparticles is
frequently advantageous, for example, because the particles resist
agglomeration, thereby promoting the formation of more evenly
distributed pockets at the surface of the medical articles of the
present invention which the therapeutic agent can occupy. Moreover,
the presence of a surface charge on the microparticles can also be
used to attract charged or polar therapeutic agents in certain
embodiments, thereby increasing drug loading.
[0040] As to composition, the microparticles can comprise ceramic,
metallic and polymeric materials, including microparticles that are
biodisintegrable and microparticles that are not (sometimes
referred to herein as biostable).
[0041] Examples of ceramic materials for use in the microparticles
of the present invention can be selected from those comprising one
or more of the following: metal oxides, including aluminum oxides
and transition metal oxides (e.g., oxides of titanium, zirconium,
hafnium, tantalum, molybdenum, tungsten, rhenium, and iridium);
silicon-based ceramics, such as those containing silicon nitrides,
silicon carbides and silicon oxides (sometimes referred to as glass
ceramics); calcium phosphate ceramics (e.g., hydroxyapatite); and
carbon-based ceramic-like materials such as carbon nitrides.
[0042] Examples of metallic materials for use in the microparticles
of the present invention can be selected from those comprising one
or more of the following: metal alloys such as cobalt-chromium
alloys, nickel-titanium alloys (e.g., nitinol),
cobalt-chromium-iron alloys (e.g., elgiloy alloys), nickel-chromium
alloys (e.g., inconel alloys), and iron-chromium alloys (e.g.,
stainless steels, which contain at least 50% iron and at least
11.5% chromium), and noble metals such as silver, gold, platinum,
palladium, iridium, osmium, rhodium, titanium, tungsten, and
ruthenium.
[0043] Examples of polymeric materials for use in the
microparticles of the present invention can be selected from those
comprising one or more of the following: polycarboxylic acid
polymers and copolymers including polyacrylic acids; acetal
polymers and copolymers; acrylate and methacrylate polymers and
copolymers (e.g., n-butyl methacrylate); cellulosic polymers and
copolymers, including cellulose acetates, cellulose nitrates,
cellulose propionates, cellulose acetate butyrates, cellophanes,
rayons, rayon triacetates, and cellulose ethers such as
carboxymethyl celluloses and hydoxyalkyl celluloses;
polyoxymethylene polymers and copolymers; polyimide polymers and
copolymers such as polyether block imides, polyamidimides,
polyesterimides, and polyetherimides; polysulfone polymers and
copolymers including polyarylsulfones and polyethersulfones;
polyamide polymers and copolymers including nylon 6,6, nylon 12,
polycaprolactams and polyacrylamides; resins including alkyd
resins, phenolic resins, urea resins, melamine resins, epoxy
resins, allyl resins and epoxide resins; polycarbonates;
polyacrylonitriles; polyvinylpyrrolidones (cross-linked and
otherwise); polymers and copolymers of vinyl monomers including
polyvinyl alcohols, polyvinyl halides such as polyvinyl chlorides,
ethylene-vinylacetate copolymers (EVA), polyvinylidene chlorides,
polyvinyl ethers such as polyvinyl methyl ethers, polystyrenes,
styrene-maleic anhydride copolymers, styrene-butadiene copolymers,
styrene-ethylene-butylene copolymers (e.g., a
polystyrene-polyethylene/butylene-polystyrene (SEBS) copolymer,
available as Kraton.RTM. G series polymers), styrene-isoprene
copolymers (e.g., polystyrene-polyisoprene-polystyrene),
acrylonitrile-styrene copolymers, acrylonitrile-butadiene-styrene
copolymers, styrene-butadiene copolymers and styrene-isobutylene
copolymers (e.g., polyisobutylene-polystyrene block copolymers such
as SIBS), polyvinyl ketones, polyvinylcarbazoles, and polyvinyl
esters such as polyvinyl acetates; polybenzimidazoles; polyalkyl
oxide polymers and copolymers including polyethylene oxides (PEO);
glycosaminoglycans; polyesters including polyethylene
terephthalates and aliphatic polyesters such as polymers and
copolymers of lactide (which includes lactic acid as well as d-,l-
and meso lactide), epsilon-caprolactone, glycolide (including
glycolic acid), hydroxybutyrate, hydroxyvalerate, para-dioxanone,
trimethylene carbonate (and its alkyl derivatives),
1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and
6,6-dimethyl-1,4-dioxan-2-one (a copolymer of polylactic acid and
polycaprolactone is one specific example); polyether polymers and
copolymers including polyarylethers such as polyphenylene ethers,
polyether ketones, polyether ether ketones; polyphenylene sulfides;
polyolefin polymers and copolymers, including polyalkylenes such as
polypropylenes, polyethylenes (low and high density, low and high
molecular weight), polybutylenes (such as polybut-1-ene and
polyisobutylene), EPDM copolymers (e.g., santoprene), ethylene
propylene diene monomer (EPDM) rubbers, poly-4-methyl-pen-1-enes- ,
ethylene-alpha-olefin copolymers, ethylene-methyl methacrylate
copolymers and ethylene-vinyl acetate copolymers; fluorinated
polymers and copolymers, including polytetrafluoroethylenes (PTFE),
poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modified
ethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidene
fluorides (PVDF); silicone polymers and copolymers; polyurethanes;
p-xylylene polymers; polyiminocarbonates; copoly(ether-esters) such
as polyethylene oxide-polylactic acid copolymers; polyphosphazines;
polyalkylene oxalates; polyoxaamides and polyoxaesters (including
those containing amines and/or amido groups); polyorthoesters;
biopolymers, such as polypeptides, proteins, polysaccharides and
fatty acids (and esters thereof), including fibrin, fibrinogen,
collagen, elastin, chitosan, gelatin, starch, glycosaminoglycans
such as hyaluronic acid; as well as blends and copolymers of the
above.
[0044] Such polymers may be provided in a variety of
configurations, including cyclic, linear and branched
configurations. Branched configurations include star-shaped
configurations (e.g., configurations in which three or more chains
emanate from a single branch point), comb configurations (e.g.,
graft polymers having a main chain and a plurality of branching
side chains), and dendritic configurations (e.g., arborescent and
hyperbranched polymers). The polymers can be formed from a single
monomer (i.e., they can be homopolymers), or they can be formed
from multiple monomers (i.e., they can be copolymers) that can be
distributed, for example, randomly, in an orderly fashion (e.g., in
an alternating fashion), or in blocks.
[0045] In certain beneficial embodiments, the polymeric materials
for use in the microparticles of the present invention can be
selected from biocompatible biodisintegrable protein materials,
which may be, for example, synthetic proteins,
genetically-engineered proteins, natural proteins or any
combination thereof. Naturally occurring proteins that may be
utilized are selected, for example, from elastin, collagen,
albumin, keratin, fibronectin, silk, silk fibroin, silk elastin,
actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III,
and any other biocompatible, biodisintegrable protein. Further
specific biocompatible, biodisintegrable protein materials are
described, for example, in U.S. Patent Appln. No. 2003/0007991.
[0046] Using stimuli sensitive protein based microparticles allows
for a high degree of control of the material making up the
microparticles and, thus, the release profile of therapeutic agents
from the microparticles. For example, in one embodiment of the
invention, protein-based silk-elastin microparticles with
associated DNA (e.g., microparticles with DNA that is entrapped,
encapsulated, adsorbed and/or absorbed) are adhered to an adhesive
region. Direct mixing of the silk-elastin microparticles with the
DNA in aqueous solution results in the association of the DNA (as
well as other drugs) with the microparticles. In general, the
higher the number of silk units in such microparticles, the higher
the degree of crosslinking that exists within the microparticles,
and thus the lower the degradation rate. The pore sizes of such
particles are typically on the order of 0.1 .mu.m, however, pore
size and swelling can be controlled by varying the number of silk
units, the pH, the temperature, and so forth.
[0047] Medical articles which can be provided in accordance with
the present invention include essentially any medical article from
which release of a therapeutic agent is desired. Examples of
medical articles include patches for delivery of therapeutic agent
to intact skin, broken skin (including wounds), and surgical sites.
Examples of medical articles also include implantable or insertable
medical devices, for example, catheters (for example, renal or
vascular catheters such as balloon catheters), guide wires,
balloons, filters (e.g., vena cava filters), stents (including
coronary vascular stents, cerebral, urethral, ureteral, bone
prosthesis, biliary, tracheal, gastrointestinal and esophageal
stents), stent grafts, cerebral aneurysm filler coils (including
Guglilmi detachable coils and metal coils), vascular grafts,
myocardial plugs, patches (e.g., vascular patches such as heart
cavity patches, gastrointestinal patches such as esophageal or
stomach patches, and urological patches such as bladder, kidney,
ureteral and urethral patches), pacemakers and pacemaker leads,
heart valves, as well as any other medical device that is implanted
or inserted into the body and from which a therapeutic agent is
released.
[0048] The medical articles of the present invention include
medical articles that are used for either systemic treatment or for
the localized treatment of any mammalian tissue or organ.
Non-limiting examples are tumors; organs including the heart,
coronary and peripheral vascular system (referred to overall as
"the vasculature"), lungs, trachea, esophagus, brain, liver,
kidney, bladder, urethra and ureters, eye, intestines, stomach,
pancreas, ovary, and prostate; skeletal muscle; smooth muscle;
breast; dermal tissue; cartilage; and bone. As used herein,
"treatment" refers to the prevention of a disease or condition, the
reduction or elimination of symptoms associated with a disease or
condition, or the substantial or complete elimination a disease or
condition. Preferred subjects are mammalian subjects and more
preferably human subjects.
[0049] For example, in accordance with one specific embodiment of
the invention, the medical device is a patch for the application of
gene therapy to heart cavities. In this particular embodiment,
microspheres are adhered to one side of the patch with mussel
protein adhesive, and plasmid DNA is disposed within the pockets
created by the microspheres after cure. On the opposite side of the
patch, the same adhesive can be used to anchor a repellant species,
for example, polyethylene glycol. The patch can be delivered, for
example, using a balloon.
[0050] In accordance with another specific embodiment of the
invention, a balloon is utilized as a substrate for an adhesive
coating. A therapeutic agent, for example a high molecular weight
therapeutic agent (e.g., plasmid DNA) and microparticles are then
applied to the adhesive coating while in a sticky state. The
balloon is subsequently used for PCTA, while at the same time
providing a therapeutic agent to the site of the lesion or
blockage. In accordance with yet another specific embodiment of the
invention, a therapeutic agent, for example a high-molecular-weight
therapeutic agent (e.g., plasmid DNA), is contacted with a
biodisintegrable adhesive region while in a sticky state, and the
resulting composition is exposed to the body via balloon or stent
insertion. Where the therapeutic agent is adhered to the adhesive
region, the adhesive region is typically biodisintegrable. Where
the therapeutic agent is not adhered to the adhesive region, the
adhesive region is typically either biodisintegrable or
biostable.
[0051] In some embodiments of the invention, an implantable or
insertable medical device is further provided with an optional
biodisintegrable protection layer to prevent premature loss of the
therapeutic agent. The biodisintegrable protection layer covers and
protects the therapeutic-containing regions of the device during
deployment, but disintegrates (e.g., dissolves or is enzymatically
or hydrolytically degraded) after being situated at a location
within a patient, thereby allowing the therapeutic agent to be
released.
[0052] The present invention is especially useful in delivering
high-molecular-weight therapeutic agents, which are defined herein
to include therapeutic agents having a molecular weight greater
than 500, typically greater than 1,000, more typically greater than
2,000, or combinations of agents which contain at least one
therapeutic agent having such molecular weights (and which can also
contain non-high-molecular-weight therapeutic agents, referred to
herein as "low-molecular-weight therapeutic agents"). "Therapeutic
agents," "pharmaceutically active agents," "pharmaceutically active
materials," "drugs" and other related terms may be used
interchangeably herein and include genetic therapeutic agents,
non-genetic therapeutic agents and cells. High and low-molecular
weight therapeutic agent can be selected from suitable members of
the lists of therapeutic agents to follow.
[0053] Exemplary non-genetic therapeutic agents for use in
connection with the present invention include: (a) anti-thrombotic
agents such as heparin, heparin derivatives, urokinase, and PPack
(dextrophenylalanine proline arginine chloromethylketone); (b)
anti-inflammatory agents such as dexamethasone, prednisolone,
corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;
(c) anti-neoplastic/antiproliferative/anti-- miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, angiopeptin, monoclonal
antibodies capable of blocking smooth muscle cell proliferation,
and thymidine kinase inhibitors; (d) anesthetic agents such as
lidocaine, bupivacaine and ropivacaine; (e) anti-coagulants such as
D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing
compound, heparin, hirudin, antithrombin compounds, platelet
receptor antagonists, anti-thrombin antibodies, anti-platelet
receptor antibodies, aspirin, prostaglandin inhibitors, platelet
inhibitors and tick antiplatelet peptides; (f) vascular cell growth
promoters such as growth factors, transcriptional activators, and
translational promotors; (g) vascular cell growth inhibitors such
as growth factor inhibitors, growth factor receptor antagonists,
transcriptional repressors, translational repressors, replication
inhibitors, inhibitory antibodies, antibodies directed against
growth factors, bifunctional molecules consisting of a growth
factor and a cytotoxin, bifunctional molecules consisting of an
antibody and a cytotoxin; (h) protein kinase and tyrosine kinase
inhibitors (e.g., tyrphostins, genistein, quinoxalines); (i)
prostacyclin analogs; (j) cholesterol-lowering agents; (k)
angiopoietins; (l) antimicrobial agents such as triclosan,
cephalosporins, aminoglycosides and nitrofurantoin; (m) cytotoxic
agents, cytostatic agents and cell proliferation affectors; (n)
vasodilating agents; (O) agents that interfere with endogenous
vasoactive mechanisms; (p) inhibitors of leukocyte recruitment,
such as monoclonal antibodies; (q) cytokines and (r) hormones.
[0054] Some exemplary non-genetic therapeutic agents include
paclitaxel, sirolimus, everolimus, tacrolimus, cladribine,
dexamethasone, estradiol, ABT-578 (Abbott Laboratories), trapidil,
liprostin, Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel
and Ridogrel.
[0055] Exemplary genetic therapeutic agents for use in connection
with the present invention include anti-sense DNA and RNA as well
as DNA coding for: (a) anti-sense RNA, (b) tRNA or rRNA to replace
defective or deficient endogenous molecules, (c) angiogenic factors
including growth factors such as acidic and basic fibroblast growth
factors, vascular endothelial growth factor, epidermal growth
factor, transforming growth factor .alpha. and .beta.,
platelet-derived endothelial growth factor, platelet-derived growth
factor, tumor necrosis factor .alpha., hepatocyte growth factor and
insulin-like growth factor, (d) cell cycle inhibitors including CD
inhibitors, and (e) thymidine kinase ("TK") and other agents useful
for interfering with cell proliferation. Also of interest is DNA
encoding for the family of bone morphogenic proteins ("BMP's"),
including BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1),
BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and
BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as
homodimers, heterodimers, or combinations thereof, alone or
together with other molecules. Alternatively, or in addition,
molecules capable of inducing an upstream or downstream effect of a
BMP can be provided. Such molecules include any of the "hedgehog"
proteins, or the DNA's encoding them.
[0056] Vectors for delivery of genetic therapeutic agents include
viral vectors such as adenoviruses, gutted adenoviruses,
adeno-associated virus, retroviruses, alpha virus (Semliki Forest,
Sindbis, etc.), lentiviruses, herpes simplex virus, replication
competent viruses (e.g., ONYX-015) and hybrid vectors; and
non-viral vectors such as artificial chromosomes and
mini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic
polymers (e.g., polyethyleneimine, polyethyleneimine (PEI)), graft
copolymers (e.g., polyether-PEI and polyethylene oxide-PEI),
neutral polymers PVP, SP1017 (SUPRATEK), lipids such as cationic
lipids, liposomes, lipoplexes, nanoparticles, or microparticles,
with and without targeting sequences such as the protein
transduction domain (PTD).
[0057] Cells for use in connection with the present invention
include cells of human origin (autologous or allogeneic), including
whole bone marrow, bone marrow derived mono-nuclear cells,
progenitor cells (e.g., endothelial progenitor cells), stem cells
(e.g., mesenchymal, hematopoietic, neuronal), pluripotent stem
cells, fibroblasts, myoblasts, satellite cells, pericytes,
cardiomyocytes, skeletal myocytes or macrophage, or from an animal,
bacterial or fungal source (xenogeneic), which can be genetically
engineered, if desired, to deliver proteins of interest.
[0058] Numerous therapeutic agents, not necessarily exclusive of
those listed above, have been identified as candidates for vascular
treatment regimens, for example, as agents targeting restenosis.
Such agents include one or more of the following: (a) Ca-channel
blockers including benzothiazapines such as diltiazem and
clentiazem, dihydropyridines such as nifedipine, amlodipine and
nicardapine, and phenylalkylamines such as verapamil, (b) serotonin
pathway modulators including: 5-HT antagonists such as ketanserin
and naftidrofuryl, as well as 5-HT uptake inhibitors such as
fluoxetine, (c) cyclic nucleotide pathway agents including
phosphodiesterase inhibitors such as cilostazole and dipyridamole,
adenylate/Guanylate cyclase stimulants such as forskolin, as well
as adenosine analogs, (d) catecholamine modulators including
.alpha.-antagonists such as prazosin and bunazosine,
.beta.-antagonists such as propranolol and
.alpha./.beta.-antagonists such as labetalol and carvedilol, (e)
endothelin receptor antagonists, (f) nitric oxide donors/releasing
molecules including organic nitrates/nitrites such as
nitroglycerin, isosorbide dinitrate and amyl nitrite, inorganic
nitroso compounds such as sodium nitroprusside, sydnonimines such
as molsidomine and linsidomine, nonoates such as diazenium diolates
and NO adducts of alkanediamines, S-nitroso compounds including low
molecular weight compounds (e.g., S-nitroso derivatives of
captopril, glutathione and N-acetyl penicillamine) and high
molecular weight compounds (e.g., S-nitroso derivatives of
proteins, peptides, oligosaccharides, polysaccharides, synthetic
polymers/oligomers and natural polymers/oligomers), as well as
C-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds and
L-arginine, (g) ACE inhibitors such as cilazapril, fosinopril and
enalapril, (h) ATII-receptor antagonists such as saralasin and
losartin, (i) platelet adhesion inhibitors such as albumin and
polyethylene oxide, (j) platelet aggregation inhibitors including
aspirin and thienopyridine (ticlopidine, clopidogrel) and GP
IIb/IIIa inhibitors such as abciximab, epitifibatide and tirofiban,
(k) coagulation pathway modulators including heparinoids such as
heparin, low molecular weight heparin, dextran sulfate and
.beta.-cyclodextrin tetradecasulfate, thrombin inhibitors such as
hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone)
and argatroban, FXa inhibitors such as antistatin and TAP (tick
anticoagulant peptide), Vitamin K inhibitors such as warfarin, as
well as activated protein C, (1) cyclooxygenase pathway inhibitors
such as aspirin, ibuprofen, flurbiprofen, indomethacin and
sulfinpyrazone, (m) natural and synthetic corticosteroids such as
dexamethasone, prednisolone, methprednisolone and hydrocortisone,
(n) lipoxygenase pathway inhibitors such as nordihydroguairetic
acid and caffeic acid, (O) leukotriene receptor antagonists, (p)
antagonists of E- and P-selectins, (q) inhibitors of VCAM-1 and
ICAM-1 interactions, (r) prostaglandins and analogs thereof
including prostaglandins such as PGE1 and PGI2 and prostacyclin
analogs such as ciprostene, epoprostenol, carbacyclin, iloprost and
beraprost, (s) macrophage activation preventers including
bisphosphonates, (t) HMG-CoA reductase inhibitors such as
lovastatin, pravastatin, fluvastatin, simvastatin and cerivastatin,
(u) fish oils and omega-3-fatty acids, (v) free-radical
scavengers/antioxidants such as probucol, vitamins C and E,
ebselen, trans-retinoic acid and SOD mimics, (w) agents affecting
various growth factors including FGF pathway agents such as bFGF
antibodies and chimeric fusion proteins, PDGF receptor antagonists
such as trapidil, IGF pathway agents including somatostatin analogs
such as angiopeptin and ocreotide, TGF-.beta. pathway agents such
as polyanionic agents (heparin, fucoidin), decorin, and TGF-.beta.
antibodies, EGF pathway agents such as EGF antibodies, receptor
antagonists and chimeric fusion proteins, TNF-.alpha. pathway
agents such as thalidomide and analogs thereof, Thromboxane A2
(TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben
and ridogrel, as well as protein tyrosine kinase inhibitors such as
tyrphostin, genistein and quinoxaline derivatives, (x) MMP pathway
inhibitors such as marimastat, ilomastat and metastat, (y) cell
motility inhibitors such as cytochalasin B, (z)
antiproliferative/antineoplastic agents including antimetabolites
such as purine analogs (e.g., 6-mercaptopurine or cladribine, which
is a chlorinated purine nucleoside analog), pyrimidine analogs
(e.g., cytarabine and 5-fluorouracil) and methotrexate, nitrogen
mustards, alkyl sulfonates, ethylenimines, antibiotics (e.g.,
daunorubicin, doxorubicin), nitrosoureas, cisplatin, agents
affecting microtubule dynamics (e.g., vinblastine, vincristine,
colchicine, paclitaxel and epothilone), caspase activators,
proteasome inhibitors, angiogenesis inhibitors (e.g., endostatin,
angiostatin and squalamine), rapamycin, cerivastatin, flavopiridol
and suramin, (aa) matrix deposition/organization pathway inhibitors
such as halofuginone or other quinazolinone derivatives and
tranilast, (bb) endothelialization facilitators such as VEGF and
RGD peptide, and (cc) blood rheology modulators such as
pentoxifylline.
[0059] Numerous additional therapeutic agents are also disclosed in
U.S. Pat. No. 5,733,925 assigned to NeoRx Corporation, the entire
disclosure of which is incorporated by reference.
[0060] As noted above, the present invention is especially useful
in delivering high-molecular-weight therapeutic agents. Examples of
high-molecular-weight therapeutic agents, not necessarily exclusive
of those listed above, include polysaccharide therapeutic agents
having a molecular weight greater than 1,000; polypeptide
therapeutic agents having a molecular weight greater than 10,000;
polynucleotides, including antisense polynucleotides, having a
molecular weight greater than 2,000, gene-encoding polynucleotides,
including plasmids, having a molecular weight greater than 500,000;
viral and non-viral particles having a diameter greater than about
50 nanometers, and cells.
[0061] A "polynucleotide" is a nucleic acid polymer. A
polynucleotide can include both double- and single-stranded
sequences, and can include naturally derived and synthetic DNA
sequences. The term also includes sequences that include any of the
known base analogs of DNA and RNA, and includes modifications, such
as deletions, additions and substitutions (generally conservative
in nature) to native sequences.
[0062] Typical polynucleotide therapeutic agents include the
genetic therapeutic agents specifically listed above, and more
generally include DNA encoding for various polypeptide and protein
products including those previously listed. Some additional
examples of polynucleotide therapeutic agents include DNA encoding
for the following: cytokines such as colony stimulating factors
(e.g., granulocyte-macrophage colony-stimulating factor), tumor
necrosis factors (e.g., fas ligand) and interleukins (e.g., IL-10,
an anti-inflammatory interleukin), as well as protease inhibitors,
particularly serine protease inhibitors (e.g., SERP-1), tissue
inhibiting metalloproteinases (e.g., TIMP-1, TIMP-2, TIMP-3,
TIMP-4), monocyte chemoattractant proteins (e.g., MCP-1), protein
kinase inhibitors including cyclin-dependent kinase inhibitors
(e.g., p27, p21), endogenous and inducible nitric oxide synthase,
CO-generating enzymes, such as hemoxygenases, which catalyze the
oxidation of heme into the biologically active molecules iron
biliverdin and CO (e.g., HOI-1), antiproliferative compounds, such
as HKIS in a transdominant mutant peptide form, which are capable
of interfering with the ability of endogenous HKIS to phosphorylate
p27 thereby enhancing cell cycle arrest, as well as derivatives of
the foregoing.
[0063] The term "polypeptide" refers to a polymer of amino acid
residues. Both full-length proteins and fragments thereof are
encompassed by the definition. The terms also include
modifications, such as deletions, additions and substitutions
(generally conservative in nature), to native sequence. Exemplary
polypeptides include any of the polypeptides/proteins listed in the
preceding paragraphs.
[0064] The term "polysaccharide" refers to a polymer of
monosaccharide residues. Examples of polysaccharides include the
polysaccharides listed in the preceding paragraphs. Low and high
molecular weight heparin and dextran, including derivatives of the
same, for example, dextran sulfate salts and dextran-metal
complexes such as dextran-iron complex, are some exemplary
polysaccharides.
[0065] Hybrids of the above high-molecular-weight therapeutics
(e.g., DNA/protein hybrids and polysaccharide/protein hybrids) are
also within the scope of the present invention.
[0066] Some specific classes of therapeutic agents are
anti-proliferative agents, anti-inflammatory agents,
anti-thrombotic agents, lipid mediators, vasodilators, anti-spasm
agents, remodeling agents, endothelial-cell specific mitogens, as
well as nucleotide sequences (which may further include an
associated delivery vector) encoding for therapeutic agents having
any one or combination of these therapeutic effects. Examples
include plasmids that encode an antiproliferative protein within
the arterial walls to help prevent a recurring blockage due to
restenosis, anti-inflammatory proteins and anti-thrombotic
polysaccharides designed to prevent blood clotting.
[0067] A wide range of therapeutic agent loadings can be used in
connection with medical articles of the present invention, with the
therapeutically effective amount being readily determined by those
of ordinary skill in the art and ultimately depending, for example,
upon the condition to be treated, the age, sex and condition of the
patient, the nature of the therapeutic agent, the nature of the
release region, the nature of the medical article, and so
forth.
[0068] Although various embodiments are specifically illustrated
and described herein, it will be appreciated that modifications and
variations of the present invention are covered by the above
teachings and are within the purview of the appended claims without
departing from the spirit and intended scope of the invention.
* * * * *